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Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 300-305
Comparison of Interleukin-1 Expression by In Situ Hybridization in
Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma
By
Martha Q. Lacy,
Kathleen A. Donovan,
Julie K. Heimbach,
Gregory J. Ahmann, and
John A. Lust
From the Division of Hematology and Internal Medicine, Mayo Clinic,
Rochester, MN.
 |
ABSTRACT |
We investigated whether interleukin-1 (IL-1) is differentially
expressed in plasma cells from monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patients because IL-1
appears to play a major role in the development of lytic bone lesions,
the major clinical feature distinguishing MGUS from myeloma. In situ
hybridization (ISH) for IL-1 was performed using bone marrow
aspirates from 51 MM, 7 smoldering MM, 21 MGUS, and 5 normal control
samples. Using the ISH technique IL-1 mRNA was detectable in the
plasma cells from 49 of 51 patients with active myeloma and 7 of 7 patients with smoldering myeloma. In contrast, 5 of 21 patients with
MGUS and 0 of 5 normal controls had detectable IL-1 message. Bone
lesions were present in 40 of the 51 MM patients analyzed, and all 40 patients had IL-1 mRNA by ISH. These results show that greater than
95% of MM patients but less than 25% of MGUS patients are positive
for IL-1 production. In the future, continued follow-up of IL-1
positive and negative MGUS patients should determine whether aberrant
expression of plasma cell IL-1 is predictive of those MGUS patients
that will eventually progress to active myeloma.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
MULTIPLE MYELOMA (MM) is a universally
fatal B-cell malignancy accounting for 1% to 2% of all cancer
deaths.1 MM is recognized clinically by the proliferation
of malignant plasma cells in the bone marrow, the detection of a serum
or urine monoclonal protein, anemia, hypercalcemia, renal
insufficiency, and lytic bone lesions.2 Monoclonal
gammopathy of undetermined significance (MGUS) is characterized by a
monoclonal protein in the serum or urine without the other clinical
features of MM. MGUS patients are asymptomatic and have stable
M-protein measurements.3 MGUS is more common than myeloma
occurring in 1% of the population over age 50 and 3% over age
70.4 It is of great clinical importance to distinguish
patients with myeloma from individuals with MGUS because MGUS patients
may be safely observed without chemotherapy.2 In long-term
follow-up of 241 patients with MGUS, approximately 16% went on to
develop MM.3
The molecular changes that result in the progression of MGUS to myeloma
are currently unknown. However, a potential role for the acquired
expression of various cytokines, oncogenes, and viruses has been
implicated.5,6 Although interleukin-1 (IL-1 ) is not
produced by normal plasma cells, several investigators have detected
the production of IL-1 by myeloma marrow cells.7-11 IL-1 is known to be a potent osteoclast activating factor and appears to play a major role in the development of lytic bone lesions,7,8,11 the major clinical feature distinguishing MGUS from myeloma.2 Torcia et al11 have shown a
dose response between the level of IL-1 produced by marrow cells
from patients with myeloma and osteoclast activating factor activity.
IL-1 is also a potent inducer of other cytokines including IL-6,
which is a major growth factor for myeloma cells.10 Based
on these observations, IL-1 could be a central cytokine involved in
the progression of MGUS to myeloma.
We recently showed, in a small number of patients, that IL-1
expression appears to be able to differentiate between patients with
MGUS and MM using cell sorting to enrich for plasma cells followed by
reverse transcriptase-polymerase chain reaction (RT-PCR).12 Confirmation that the IL-1-expressing cells were plasma cells was
accomplished using an in situ hybridization (ISH) assay specific for
IL-1 expression on bone marrow cells from a myeloma
patient.12 Based on this earlier work, we have now
investigated whether differences in IL-1 expression could be
detected in monoclonal plasma cells from a large number of patients
with either MGUS or myeloma using ISH. ISH has the advantage of
simultaneous detection of cytokine expression and morphologic
identification of the cytokine producing cell from unsorted cell
populations. Our results show that IL-1 mRNA is undetectable in the
plasma cells from the majority of patients with MGUS but is expressed
by the plasma cells from virtually all patients with MM.
| |
MATERIALS AND METHODS |
Patients.
Bone marrow aspirates were obtained from 79 patients with plasma cell
proliferative disorders consisting of 51 patients with MM, 7 patients
with smoldering myeloma (SMM), 21 patients with MGUS, and 5 normal
controls. Diagnoses were established using previously published
criteria for MGUS, SMM, and MM.2,13 All samples used in
this study were obtained from patients with informed consent according
to Institutional Review Board Guidelines.
ISH for IL-1.
ISH for IL-1 expression was performed as previously
described.12 Briefly, paraformaldehyde fixed cells from
Ficoll-Hypaque density gradient purified bone marrow aspirates were
hybridized with a digoxigenin-11-dUTP-labeled (Boehringer Mannheim,
Indianapolis, IN) antisense oligonucleotide probe specific for the
human IL-1 gene. For each patient, a positive and negative control
were run using commercially available fluorescein isothiocyanate
(FITC)-labeled kappa and lambda probes (DAKO Corp, Carpinteria, CA). A
blank slide without probe was run on each patient to control for
nonspecific staining. An antiprobe antibody was added
(anti-Digoxigenin-AP for the IL-1 and blanks; anti-FITC-AP for the
kappa and lambda). The reactions were developed in NBT/BCIP.
Hematoxylin was used as a nuclear counterstain. Slides were examined
microscopically, and plasma cells were scored as positive or negative
for IL-1 mRNA. Because MGUS specimens often contain a mixture of
polyclonal and monoclonal plasma cells, a patient was considered to be
positive for IL-1 expression by ISH if greater than or equal to 50%
of the plasma cells were IL-1 positive. Each slide was scored
independently by three different readers (M.Q.L., K.A.D., J.A.L.).
Flow cytometry and RT-PCR for IL-1 expression.
Flow cytometry and RT-PCR were performed as previously
described.12 Briefly, 25 to 30 million mononuclear cells
from bone marrow aspirates were stained with a FITC-conjugated
monoclonal antibody to CD45 and a phycoerythrin (PE)-conjugated
antibody against CD38 (Becton Dickinson, San Jose, CA). Using a FACStar Plus flow cytometer, debris and nucleated red blood cells were excluded
by gating on the larger cells as defined by intermediate-to-high forward and negative-to-intermediate orthogonal light scatter. The
CD38+/CD45 region was collected and
contained greater than 95% plasma cells for all patients. This was
confirmed morphologically.12 Subsequently, messenger RNA
was isolated from 105 to 106 unsorted (U) and
sorted (S) CD38+/CD45 cells.
Oligo-dT-purified mRNA was reverse transcribed using AMV reverse
transcriptase (Amersham, Arlington Heights, IL). Subsequently, 1 µL of the first-strand cDNA template reaction was added to a standard PCR mix with oligonucleotide primers specific for the full-length cDNA of IL-1 (Clontech, Palo Alto, CA). Actin-specific primers were used as a control as previously described.12
Fidelity of the amplified sequences was confirmed by fragment size
comparison with a known control in all experiments and Southern
blotting using an Applied Biosystems (Foster City, CA) Model 394 DNA-synthesized oligonucleotide probe
(5 -AGACATCACCAAGCTTTTTTGCTGTGAGTC-3) contained within the
PCR fragments in selected cases.12,14 Reactions without DNA
template were run with every experiment as a negative control (data not
shown).
| |
RESULTS |
Contrast in IL-1 expression between patients with MGUS
and MM.
Results from several representative ISH assays are detailed in
Figs 1 through
3. Plasma cells from a patient with MM
were positive for IL-1 and lambda expression as shown by the strong brown-black cytoplasmic staining (Fig 1A and B). The myeloma cells were
negative for kappa expression (Fig 1C). All slides were
counter-stained in hematoxylin. Plasma cells from a patient with MGUS
were negative for lambda and IL-1 (Fig 2A and B) but positive for
kappa expression (Fig 2C). In Fig 3, plasma cells from this MGUS
patient were positive for IL-1 expression. The other leukocytes in
the IL-1 panel are negative for IL-1 expression and serve as a
useful control.
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| Fig 1.
ISH for IL-1 in a patient with MM. (A) IL-1; (B)
lambda; (C) kappa. Plasma cells from a patient with MM were negative
for kappa expression but positive for IL-1 and lambda expression as
shown by the strong brown-black cytoplasmic staining. All slides were
counter-stained in hematoxylin.
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| Fig 2.
ISH for IL-1 in a patient with MGUS. (A) IL-1; (B)
lambda; (C) kappa. Plasma cells from this MGUS patient were positive
for kappa expression and negative for lambda and IL-1.
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| Fig 3.
ISH for IL-1 in a patient with MGUS. Plasma cells from
this MGUS patient were positive for IL-1.
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Using the ISH technique IL-1 mRNA was detectable in the plasma cells
from 49 of 51 patients with active myeloma
(Table 1). In contrast, only 5 of 21 patients with MGUS showed detectable IL-1 expression by ISH
(P < .0001). None of the plasma cells from the 5 normal
controls had detectable IL-1 mRNA. Interestingly, 7 of 7 patients
with SMM had detectable IL-1 message (Table 1).
Bone lesions were present in 40 of the 51 MM patients analyzed, and all
40 patients with bone lesions had IL-1 mRNA detected in the
monoclonal plasma cells by ISH (Table
2). In addition, 9 of the 11 patients in whom bone lesions were
undetectable on a metastatic bone survey were IL-1 positive. No
patient with detectable bone lesions was found to be IL-1 negative.
Correlation of ISH and RT-PCR for IL-1 expression.
Fourteen of the patients had concurrent marrow aspirates sorted by flow
cytometry using anti-CD38 and anti-CD45 antibodies. Messenger RNA was
isolated from 105 to 106 unsorted (U) and
sorted CD38+/CD45 (S) cells.
Subsequently, RT-PCR with specific cytokine primers was performed to
detect the presence of message for IL-1 and actin. In
Fig 4, IL-1 mRNA was detectable in
sorted CD38+/CD45 cells from a myeloma
patient but not from a MGUS patient. Nine patients had detectable
IL-1 mRNA in the plasma cells by both techniques including one
patient with MGUS and eight with MM (Table 3). Five patients had no detectable IL-1 mRNA in the plasma cells by
either technique (Table 3). This group included four patients with MGUS
and one patient with MM. All patients that were positive by ISH were
also found to be positive by RT-PCR. Of note, all unsorted bone marrow
populations contained IL-1 expressing cells by RT-PCR. Therefore, it
is important to use a technique that allows for significant
purification of the cells of interest (ie, flow cytometric sorting) or
one that allows for visual identification of the IL-1 expressing
cells (ie, ISH).
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| Fig 4.
Cytokine detection by flow cytometry/RT-PCR. Marrow
aspirates were sorted by flow cytometry using anti-CD38 and anti-CD45
antibodies. Messenger RNA was isolated from 105 to
106 unsorted (U) and sorted
CD38+/CD45 (S) cells. Subsequently, RT-PCR
with specific cytokine primers was performed to detect the presence of
message for IL-1 and actin. IL-1 mRNA was detectable in sorted
CD38+/CD45cells from the myeloma patient
but not from the MGUS patient.
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| |
DISCUSSION |
In a follow-up of 241 patients with MGUS, Kyle has shown that 16% of
patients went on to develop multiple myeloma.3 Closer examination of those individuals who developed myeloma revealed that
the majority of patients remained stable for an extended period of time
and then subsequently progressed to overt myeloma over a relatively
short period.3 Based on these clinical observations, it is
likely that genetic differences exist between MGUS and myeloma in which
subsequent mutations arise in the monoclonal plasma cells leading to
active myeloma. These mutations could induce aberrant expression of
cytokines that may play a role in the transition from MGUS to
myeloma.5
In this regard, although the IL-1 gene is not expressed in normal
plasma cells, we have shown that IL-1 mRNA is expressed by myeloma
cells obtained from greater than 95% of MM patients. In contrast,
plasma cell IL-1 mRNA expression was observed in less than 25% of
MGUS patients. These results in myeloma patients are supported by
several previous studies that have detected IL-1 at both the mRNA
and protein levels.7-12 However, our studies on plasma
cells from normal individuals and MGUS patients using ISH and flow
cytometric sorting/RT-PCR are unique. Sixteen of 21 patients with MGUS
failed to express detectable IL-1 message suggesting that plasma
cell IL-1 expression may be useful to distinguish MGUS from MM.
Furthermore, if the remaining five MGUS patients that were IL-1
positive develop myeloma in the future, then upregulation of plasma
cell IL-1 production may be predictive of those MGUS patients that
will eventually progress to active myeloma.
The development of osteolytic lesions is an important clinical finding
that clearly distinguishes MGUS from myeloma,2 and IL-1
has potent osteoclast activating factor (OAF)
activity.7,8,11 Forty of the 51 myeloma patients analyzed
had osteolytic disease on a metastatic bone survey and were IL-1
positive. Nine of the remaining 11 myeloma patients and 7 of 7 smoldering myeloma patients with a negative bone survey were positive
for IL-1 expression as well. These patients may exhibit osteolytic
disease in the future. A subgroup of patients present with active
myeloma in which bone lesions are absent at diagnosis but subsequently
develop over time. For example, one of the SMM patients studied was
found to be positive for IL-1 expression 2 years before bone lesions were detectable on his bone survey. A potential explanation may be that
plasma cells from MM patients without bone lesions at diagnosis produce
quantitatively less IL-1 when compared to myeloma patients with bone
lesions at diagnosis. Alternatively, it may take several years between
the time patients develop IL-1 producing monoclonal plasma cells and
bone lesions that can be detected on a standard metastatic bone survey.
Torcia et al11 have shown a critical role for IL-1 in
the pathogenesis of bone disease in myeloma by showing that the OAF activity of myeloma cells from patients is almost completely related to
IL-1. Using the fetal rat long-bone tissue culture assay, they
showed that the OAF activity of culture supernatants from unfractionated bone marrow cells from myeloma patients correlated with
the IL-1 content (r = .949). Furthermore, the OAF activity could be completely abolished by IL-1 receptor antagonist, soluble IL-1
receptor type I or II, or neutralizing anti-IL-1 antibodies but not
anti-IL-6 antibodies.11 In a mouse model, Hawley and colleagues introduced an IL-1 cDNA into an IL-6-dependent murine B-cell line by retroviral-mediated gene transfer.15 After
injection of these IL-1-producing B-cells into syngeneic mice, these
cells were shown to "home" to the bone marrow and produce
metastatic bone lesions. By comparison, intravenous injection of
autonomously growing B-cell lines generated in vitro by retroviral
insertion of an IL-6 cDNA rarely resulted in bone marrow or bone
metastases.15 Subsequent work has shown that aberrant
expression of IL-1 can alter adhesion molecules such as ICAM and CD44
on the surface of mouse plasmacytoma cells.16 A similar
mechanism may occur in human myeloma in which aberrant expression of
IL-1 induces increased expression of adhesion molecules such as
VLA-4, CD44, CD54, CD56, and other surface molecules.17-21
In addition, the localization of myeloma cells in the bone marrow is
also dependent on their requirement for other cytokines such as IL-6
that are produced in the bone marrow microenvironment.
In summary, IL-1 has potent osteoclast activating factor activity,
can increase the expression of adhesion molecules, and can induce
paracrine IL-6 production (Fig 5). The
increased production of adhesion molecules could explain why myeloma
cells are found predominantly in the bone marrow. Subsequently, these
"fixed" monoclonal plasma cells could now stimulate osteoclasts
through the production of IL-1 and paracrine generation of IL-6
resulting in osteolytic disease (Fig 5).
The cause of acquired IL-1 expression in myeloma is unknown.
However, the IL-1 gene is highly inducible and its expression can be
affected by many microbial and cellular products.22
Recently, a role for Kaposi's sarcoma-associated herpesvirus (KSHV)
in the pathogenesis of myeloma has been reported.6 Although
it has not been shown for KSHV, Epstein-Barr virus (EBV), human
immunodeficiency virus-1 (HIV-1), and respiratory syncytial virus (RSV)
have been shown to upregulate IL-1 expression either by directly
interacting with genomic sequences or indirectly by altering levels of
transcription factors involved in IL-1 expression.23-25
Of note, subsequent reports by other investigators have failed to
confirm the presence of KSHV in myeloma specimens.26 If
KSHV is involved in the pathogenesis of myeloma, it would not be
unlikely that it could play a role either directly or indirectly in the
aberrant expression of the IL-1 gene.
Our data show that the majority of patients with MGUS are negative for
IL-1 expression but virtually all myeloma patients are positive for
IL-1 production. In the future, continued follow-up of IL-1
positive and negative MGUS patients should determine whether aberrant
expression of IL-1 by monoclonal plasma cells is a critical event in
the transition of MGUS to myeloma. Because MGUS is relatively common in
the general population and myeloma is incurable in virtually all cases,
identification of those MGUS patients likely to progress to active
myeloma will be important in the development of new therapeutic
strategies. For example, prevention or delay of the transition from
MGUS to myeloma with an effective chemopreventive agent27
may have a major impact on the treatment of patients with monoclonal
gammopathies.
| |
FOOTNOTES |
Submitted April 14, 1998;
accepted September 2, 1998.
Supported by Grant No. CA62242 from the National Institutes of Health
and the Eastern Cooperative Oncology Group (ECOG).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to John A. Lust, MD, PhD, Division of
Hematology, Mayo Clinic, Rochester, MN 55905.
| |
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Top
Abstract
Introduction